Dr. Zeenat Safdar is an adult pulmonologist and assistant professor of Medicine at Baylor College of Medicine. Her long-term goal is to become a productive translational researcher with federally-funded research projects. The Baylor Pulmonary Hypertension Center is the largest PH center in Texas with more than 500 PAH patients. The proposed didactic training program specifically designed for Dr. Safdar includes participation in the Clinical Scientist Training Program (CSTP;K30-funded) leading to a Master's Degree followed by Ph.D in Clinical Investigation, formal mentoring by a primary mentor and a multidisciplinary advisory committee, and courses in advanced biostatistics, research design, epidemiology and ethics. She will obtain hands-on training in (1) immunohistochemistry techniques in transplanted lungs, (2) ELISA, RIA and flow cytometry, and (3) conducting and analyzing a prospective randomized clinical trial from inception to completion. PAH is a lethal disease characterized by remodeling of pulmonary arterioles with hypertrophy and collagen deposition. Aldosterone is a key neurohormonal factor that augments vascular fibrosis. Biosynthesis of aldosterone was documented in human pulmonary artery endothelial cells. Our preliminary data showing an elevation in the circulating aldosterone levels in a subset of PAH subjects suggest that renin-angiotensin- aldosterone system (RAAS) is dysregulated in PAH. Preliminary data in 12 PAH subjects from our laboratory showed that elevated collagen marker (PIIINP) correlated with worse functional status and hemodynamic data. Recent evidence suggests that aldosterone pro-fibrotic effects are mediated through TGF-beta-Smad2/3 signaling. New preliminary data showed increased expression of phosphorylated Smad2 in peripheral blood monocytes from a PAH patient suggesting that PAH may be associated with activation of the TGF-beta- Smad2/3 signaling cascade. Collectively, this data underscore the importance of studying RAAS and down- stream signaling in PAH. Specific Aim 1 will test the hypothesis that the RAAS is activated to a greater degree in PAH as compared to age- and gender-matched normal controls and that activation of RAAS/TGF- beta/Smad2/3 signaling is a marker for worse clinical outcomes in PAH subjects. Specific Aim 2 will test two interrelated hypotheses in PAH patients: first circulating biomarkers of collagen, indices of collagen degrada- tion and activation of theTGF-beta/Smad2/3 system will be present compared to age- and gender-matched controls;second, these levels will correlate with pulmonary vascular resistance and circulating levels of aldos- terone. Specific Aim 3 will test the hypothesis that treatment of PAH subjects with an aldosterone receptor antagonist, spironolactone, is associated with reduction in circulating biomarkers of collagen synthesis and/or collagen degradation and reduced TGF-beta-Smad2/3 signaling. This award will guarantee the protected time needed for Dr. Safdar's development into an independent clinical investigator. Completion of this project will advance our understanding of some of the mechanisms that underlie disease worsening in PAH. PUBLIC HEALTH RELEVANCE: Importance of the Knowledge to be gained Pulmonary arterial hypertension (PAH), a progressive disease, leads to right heart failure and largely affects young females. Our study will test the clinical use of spironolactone (a diuretic) in PAH that may fundamentally change the current clinical approach to patients with this disease. In addition, our study will test new biomarker panel in a large group of PAH patients and may lead to new diagnostic tests that may help identify patients at risk of poor outcome.